As one scientist described it, “. . . individual genes are not particularly clever—this one cares only about that molecule, that one only about some other molecule . . . But that simplicity is no barrier to building enormous complexity. If you can build an ant colony with just a few different kinds of simpleminded ants (workers, drones, and the like), think about what you can do with 30,000 cascading genes, deployed at will.”
The geneticist Antoine Danchin once used the parable of the Delphic boat to describe the process by which individual genes could produce the observed complexity of the natural world. In the proverbial story, the oracle at Delphi is asked to consider a boat on a river whose planks have begun to rot. As the wood decays, each plank is replaced, one by one—and after a decade, no plank is left from the original boat. Yet, the owner is convinced that it is the same boat. How can the boat be the same boat—the riddle runs—if every physical element of the original has been replaced?
The answer is that the “boat” is not made of planks but of the relationship between planks. If you hammer a hundred strips of wood atop each other, you get a wall; if you nail them side to side, you get a deck; only a particular configuration of planks, held together in particular relationship, in a particular order, makes a boat.
Genes operate in the same manner. Individual genes specify individual functions, but the relationship among genes allows physiology. The genome is inert without these relationships. That humans and worms have about the same number of genes—around twenty thousand—and yet the fact that only one of these two organisms is capable of painting the ceiling of the Sistine Chapel suggests that the number of genes is largely unimportant to the physiological complexity of the organism. “It is not what you have,” as a certain Brazilian samba instructor once told me, “it is what you do with it.”
Perhaps the most useful metaphor to explain the relationship between genes, forms, and functions is one proposed by the evolutionary biologist and writer Richard Dawkins. Some genes, Dawkins suggests, behave like actual blueprints. A blueprint, Dawkins continues, is an exact architectural or mechanical plan, with a one-to-one correspondence between every feature of that plan and the structure that it encodes. A door is scaled down precisely twenty times, or a mechanical screw is placed precisely seven inches from the axle. “Blueprint” genes, by that same logic, encode the instructions to “build” one structure (or protein). The factor VIII gene makes only one protein, which serves mainly one function: it enables blood to form clots. Mutations in factor VIII are akin to mistakes in a blueprint. Their effect, like a missing doorknob or forgotten widget, is perfectly predictable. The mutated factor VIII gene fails to enable normal blood clotting, and the resulting disorder—bleeding without provocation—is the direct consequence of the function of the protein.
The vast majority of genes, however, do not behave like blueprints. They do not specify the building of a single structure or part. Instead, they collaborate with cascades of other genes to enable a complex physiological function. These genes, Dawkins argues, are not like blueprints, but like recipes. In a recipe for a cake, for instance, it makes no sense to think that the sugar specifies the “top,” and the flour specifies the “bottom”; there is usually no one-to-one correspondence between an individual component of a recipe and one structure. A recipe provides instructions about process.
A cake is a developmental consequence of sugar, butter, and flour meeting each other in the right proportion, at the right temperature, and the right time. Human physiology, by analogy, is the developmental consequence of certain genes intersecting with other genes in the right sequence, in the right space. A gene is one line in a recipe that specifies an organism. The human genome is the recipe that specifies a human.
By the early 1970s, as biologists began to decipher the mechanism by which genes were deployed to generate the astounding complexities of organisms, they also confronted the inevitable question of the intentional manipulation of genes in living beings. In April 1971, the US National Institutes of Health organized a conference to determine whether the introduction of deliberate genetic changes in organisms was conceivable in the near future. Provocatively titled Prospects for Designed Genetic Change, the meeting hoped to update the public on the possibility of gene manipulations in humans, and consider the social and political implications of such technologies.
No such method to manipulate genes (even in simple organisms) was available in 1971, the panelists noted—but its development, they felt confident, was only a matter of time. “This is not science fiction,” one geneticist declared. “Science fiction is when you [. . .] can’t do anything experimentally . . . it is now conceivable that not within 100 years, not within 25 years, but perhaps within the next five to ten years, certain inborn errors . . . will be treated or cured by the administration of a certain gene that is lacking—and we have a lot of work to do in order to prepare society for this kind of change.”
If such technologies were invented, their implications would be immense: the recipe of human instruction might be rewritten. Genetic mutations are selected over millennia, one scientist observed at the meeting, but cultural mutations can be introduced and selected in just a few years. The capacity to introduce “designed genetic changes” in humans might bring genetic change to the speed of cultural change. Some human diseases might be eliminated, the histories of individuals and families changed forever; the technology would reshape our notions of heredity, identity, illness, and future. As Gordon Tomkins, the biologist from UCSF, noted: “So for the first time, large numbers of people are beginning to ask themselves: What are we doing?”
A memory: It is 1978 or ’79, and I am about eight or nine. My father has returned from a business trip. His bags are still in the car, and a glass of ice water is sweating on a tray on the dining room table. It is one of those blistering afternoons in Delhi when the ceiling fans seem to slosh heat around the room, making it feel even warmer. Two of our neighbors are waiting for him in the living room. The air seems tense with anxiety, although I cannot discern why.
My father enters the living room, and the men talk to him for a few minutes. It is, I sense, not a pleasant conversation. Their voices rise and their words sharpen, and I can make out the contours of most of the sentences, even through the concrete walls of the adjacent room, where I am supposed to be doing homework.
Jagu has borrowed money from both of them—not large sums, but enough to bring them to our house, demanding repayment. He has told one of the men that he needs the cash for medicines (he has never been prescribed any), and the other man that he needs it to buy a train ticket to Calcutta to visit his other brothers (no such trip has been planned; it would be impossible for Jagu to travel alone). “You should learn to control him,” one of the men says accusingly.
My father listens silently, patiently—but I can feel the fiery meniscus of rage rising in him, coating his throat with bile. He walks to the steel closet, where we keep the household cash, and brings it to the men, making a point of not bothering to count the notes. He can spare a few extra rupees; they should keep the change.
By the time the men leave, I know that there will be a bruising altercation at home. With the instinctual certainty of wild animals that run uphill before tsunamis, our cook has left the kitchen to summon my grandmother. The tension between my father and Jagu has been building, thickening, for a while: Jagu’s behavior at home has been particularly disruptive in the last few weeks—and this episode seems to have pushed my father beyond some edge. His face is hot with embarrassment. The fragile varnish of class and normalcy that he has struggled so hard to seal is being cracked open, and the secret life of his family is pouring out through the fissures. Now the neighbors know of Jagu’s madness, of his confabulations. My father has been shamed in their eyes: he is cheap, mean, hard-hearted, foolish, unable to control his brother. Or worse: defiled by a mental illness that runs in his family.
He walks into Jagu’s room and yanks him bodily off the bed. Jagu w
ails desolately, like a child who is being punished for a transgression that he does not understand. My father is livid, glowing with anger, dangerous. He shoves Jagu across the room. It is an inconceivable act of violence for him; he has never lifted a finger at home. My sister runs upstairs to hide. My mother is in the kitchen, crying. I watch the scene rise to its ugly crescendo from behind the living room curtains, as if watching a film in slow motion.
And then my grandmother emerges from her room, glowering like a she-wolf. She is screaming at my father, doubling-down on his violence. Her eyes are alight like coals, her tongue forked with fire. Don’t you dare touch him.
“Get out,” she urges Jagu, who retreats quickly behind her.
I have never seen her more formidable. Her Bengali furls backward, like a fuse, toward its village origins. I can make out some words, thick with accent and idiom, sent out like airborne missiles: womb, wash, taint. When I piece the sentence together, its poison is remarkable: If you hit him, I will wash my womb with water to clean your taint. I will wash my womb, she says.
My father is also frothing with tears now. His head hangs heavily. He seems infinitely tired. Wash it, he says under his breath, pleadingly. Wash it, clean it, wash it.
* * *
I. This begs the question of how the first asymmetric organisms appeared in the natural world. We do not know, and perhaps we never will. Somewhere in evolutionary history, an organism evolved to separate the functions of one part of its body from another. Perhaps one end faced a rock, while the other faced the ocean. A lucky mutant was born with the miraculous ability to localize a protein to the mouth end, and not the foot end.Discriminating mouth from foot gave that mutant a selective advantage: each asymmetric part could be further specialized for its particular task, resulting in an organism more suited to its environment. Our heads and tails are the fortunate descendants of that evolutionary innovation.
II. The death-defying function of BCL2 was also discovered by David Vaux and Suzanne Cory in Australia.
PART THREE
* * *
“THE DREAMS OF GENETICISTS”
Sequencing and Cloning of Genes
(1970–2001)
Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.
—Sydney Brenner
If we are right . . . it is possible to induce predictable and hereditary changes in cells. This is something that has long been the dream of geneticists.
—Oswald T. Avery
“Crossing Over”
What a piece of work is a man! How noble in reason, how infinite in faculties, in form and moving how express and admirable, in action how like an angel, in apprehension how like a god!
—William Shakespeare, Hamlet, act 2, scene 2
In the winter of 1968, Paul Berg returned to Stanford after an eleven-month sabbatical at the Salk Institute in La Jolla, California. Berg was forty-one years old. Built powerfully, like an athlete, he had a manner of walking with his shoulders rolling in front of him. He had a remnant trace of his Brooklyn childhood in his habits—the way, for instance, he might raise his hand and begin his sentence with the word look when provoked by a scientific argument. He admired artists, especially painters, and especially the abstract expressionists: Pollock and Diebenkorn, Newman and Frankenthaler. He was entranced by their transmutation of old vocabularies into new ones, their ability to repurpose essential elements from the tool kit of abstraction—light, lines, forms—to create giant canvases pulsing with extraordinary life.
A biochemist by training, Berg had studied with Arthur Kornberg at Washington University in St. Louis and moved with Kornberg to set up the new department of biochemistry at Stanford. Berg had spent much of his academic life studying the synthesis of proteins—but the La Jolla sabbatical had given him a chance to think about new themes. Perched high on a mesa above the Pacific, often closed in by a dense wall of morning fog, the Salk was like an open-air monk’s chamber. Working with Renato Dulbecco, the virologist, Berg had focused on studying animal viruses. He had spent his sabbatical thinking about genes, viruses, and the transmission of hereditary information.
One particular virus intrigued Berg: Simian virus 40, or SV40 for short—“simian” because it infects monkey and human cells. In a conceptual sense, every virus is a professional gene carrier. Viruses have a simple structure: they are often no more than a set of genes wrapped inside a coat—a “piece of bad news wrapped in a protein coat,” as Peter Medawar, the immunologist, had described them. When a virus enters a cell, it sheds its coat, and begins to use the cell as a factory to copy its genes, and manufacture new coats, resulting in millions of new viruses budding out of the cell. Viruses have thus distilled their life cycle to its bare essentials. They live to infect and reproduce; they infect and reproduce to live.
Even in a world of distilled essentials, SV40 is a virus distilled to the extreme essence. Its genome is no more than a scrap of DNA—six hundred thousand times shorter than the human genome, with merely seven genes to the human genome’s 21,000. Unlike many viruses, Berg learned, SV40 could coexist quite peaceably with certain kinds of infected cells. Rather than producing millions of new virions after infection—and often killing the host cell as a result, as other viruses do—SV40 could insert its DNA into the host cell’s chromosome, and then lapse into a reproductive lull, until activated by specific cues.
The compactness of the SV40 genome, and the efficiency with which it could be delivered into cells, made it an ideal vehicle to carry genes into human cells. Berg was gripped by the idea: if he could equip SV40 with a decoy “foreign” gene (foreign to the virus, at least), the viral genome would smuggle that gene into a human cell, thereby altering a cell’s hereditary information—a feat that would open novel frontiers for genetics. But before he could envision modifying the human genome, Berg had to confront a technical challenge: he needed a method to insert a foreign gene into a viral genome. He would have to artificially engineer a genetic “chimera”—a hybrid between a virus’s genes and a foreign gene.
Unlike human genes that are strung along chromosomes, like beads on open-ended strings, SV40 genes are strung into a circle of DNA. The genome resembles a molecular necklace. When the virus infects the cell and inserts its genes into chromosomes, the necklace unclasps, becomes linearized, and attaches itself to the middle of a chromosome. To add a foreign gene into the SV40 genome, Berg would need to forcibly open the clasp, insert the gene into the open circle, and seal the ends to close it again. The viral genome would do all the rest: it would carry the gene into a human cell, and insert it into a human chromosome.I
Berg was not the only biologist thinking about unclasping and clasping viral DNA to insert foreign genes. In 1969, a graduate student working in a laboratory down the hall from Berg’s lab at Stanford, Peter Lobban, had written a thesis for his third qualifying exam in which he had proposed performing a similar kind of genetic manipulation on a different virus. Lobban had come to Stanford from MIT, where he had been an undergraduate. He was an engineer by training—or, perhaps more accurately, an engineer by feeling. Genes, Lobban argued in his proposal, were no different from steel girders; they could also be retooled, altered, shaped to human specifications, and put to use. The secret was in finding the right tool kit for the right job. Working with his thesis adviser, Dale Kaiser, Lobban had even launched preliminary experiments using standard enzymes found in biochemistry to shuttle genes from one molecule of DNA to another.
In fact, the real secret, as Berg and Lobban had independently figured out, was to forget that SV40 was a virus at all, and treat its genome as if it were a chemical. Genes may have been “inaccessible” in 1971—but DNA was perfectly accessible. Avery, after all, had boiled it in solution as a naked chemical, and it had still transmitted information between bacteria. Kornberg had added enzymes to it and made it replicate in a test tube. To insert a gene into the SV40 genome, all that Berg needed was a series of reactions. He needed an
enzyme to cut open the genome circle, and an enzyme to “paste” a piece of foreign DNA into the SV40 genome necklace. Perhaps the virus—or, rather, the information contained in the virus—would then spring to life again.
But where might a scientist find enzymes that would cut and paste DNA? The answer, as so often in the history of genetics, came from the bacterial world. Since the 1960s, microbiologists had been purifying enzymes from bacteria that could be used to manipulate DNA in test tubes. A bacterial cell—any cell, for that matter—needs its own “tool kit” to maneuver its own DNA: each time a cell divides, repairs damaged genes, or flips its genes across chromosomes, it needs enzymes to copy genes or to fill in gaps created by damage.
The “pasting” of two fragments of DNA was part of this tool kit of reactions. Berg knew that even the most primitive organisms possess the capacity to stitch genes together. Strands of DNA, recall, can be split by damaging agents, such as X-rays. DNA damage occurs routinely in cells, and to repair the split strands, cells make specific enzymes to paste the broken pieces together. One of these enzymes, called “ligase” (from the Latin word ligare—“to tie together”), chemically stitches the two pieces of the broken backbone of DNA together, thus restoring the integrity of the double helix. Occasionally, the DNA-copying enzyme, “polymerase,” might also be recruited to fill in the gap and repair a broken gene.
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